SHR Group Research Articles

Polyphenol (-)-Epigallocatechin Gallate Protection from Ischemia/Reperfusion-Induced Renal Injury in Normotensive and Hypertensive Rats

Introduction The effect of epigallocatechin gallate (EGCG) in an in vivo renal model of ischemia with reperfusion (I/R) was compared between normotensive (WKR) and hypertensive (SHR) rats. Methods WKR (groups I, II, III) and SHR groups (groups IV, V, VI) were divided into three types. Groups I and IV were sham-operated animals; groups II and V were subjected to 45 minutes of renal I/R; and groups III and VI received 10 mg/kg EGCG intravenously at the time of reperfusion. Three days after renal I/R, we compared renal function markers, malondialdehyde (MDA), and histologic changes. Results Following renal I/R, levels of blood urea nitrogen (BUN) and serum creatinine (sCr) were increased and serum creatinine clearance (CrCl) decreased in group V compared to group II ( P < .001). Those receiving EGCG treatment (groups III and VI) had decreased BUN and sCr compared to non-EGCG I/R groups ( P < .001), but not surprisingly, higher than sham groups. CrCl was lowest in the SHR groups. The MDA was significantly decreased after EGCG treatment ( P = .028 in group III, P = .002 in group VI). Following renal I/R, tissue necrosis was more severe among SHR ( P < .001). However, the ratio of regeneration to damage significantly increased in SHR after EGCG treatment. Conclusions The reperfusion injury was greater among SHR compared with WKR in terms of renal function, lipid peroxidation, and tissue damage. EGCG treatment significantly ameliorated renal impairment and promoted tissue regeneration following renal I/R.

Mineralocorticoid Treatment Upregulates the Hypothalamic Vasopressinergic System of Spontaneously Hypertensive Rats

Mineralocorticoid effects in the brain include the control of cardiovascular functions, induction of salt appetite, interaction with the vasoactive neuropeptides arginine vasopressin (AVP) and angiotensin II and development or aggravation of hypertension. In this regard, mineralocorticoids may play a pathogenic role in rats with a genetic form of hypertension (spontaneously hypertensive rats, SHR). Our objective was to compare the response of the hypothalamic vasopressinergic system to mineralocorticoid administration in SHR and control Wistar-Kyoto (WKY) rats. Sixteen-week-old male SHR showing a systolic blood pressure of 190 ± 5 mm Hg and normotensive WKY rats (130 ± 5 mm Hg) were treated subcutaneously with oil vehicle or a single 10-mg dose of deoxycorticosterone acetate (DOCA). After 2 h, rats were sacrificed and brains prepared for immunocytochemistry of Fos and vasopressin V1a receptor (V1aR) and for non-isotopic in situ hybridization of AVP mRNA. In the basal state, SHR demonstrated a higher number of AVP mRNA- and V1aR-immunopositive cells in the magnocellular division of the paraventricular hypothalamic nucleus (PVN) than WKY rats. After DOCA injection, SHR responded with a significant increase in both parameters with respect to vehicle-injected SHR. In WKY rats, DOCA was without effect on AVP mRNA although it increased the number of V1aR-positive cells. Changes in the number of Fos-positive nuclei were measured in the PVN, median preoptic nucleus (MnPO) and organum vasculosum of the lamina terminalis (OVLT), a circumventricular region showing anatomical connections with the PVN. In vehicle-injected rats, the PVN of SHR showed a higher number of Fos-positive nuclei than in WKY rats, whereas after DOCA treatment, a significant increment occurred in the OVLT but not in the PVN or MnPO of the SHR group only. These data suggest that the enhanced response of the vasopressinergic system to mineralocorticoids may contribute to the abnormal blood pressure of SHR.

Genetic model of myocardial hypertrophy without elevated blood pressure in rats

A population of fourth-, fifth-, and sixth-generation hybrids obtained by crossing SI IR and WKY rats was studied. These hybrids were a basis for obtaining a genetic model of myocardial hypertrophy (МH) without elevated blood pressure (BP). To reveal the given phenotype (MH without elevated BP), the degree of MH was noninvasively estimated by vectorocardiography in combination with noninvasive BP measurement on the caudal artery. Systolic BP in male hybrids of die fourth and fifth generation was 127 ± 3 and 123 ± 3 mm Hg, respectively, which was much lower than that in male rats of the progenitor line SHR (183 ±5 mm Hg) and practically equal to that in rats of the progenitor line WKY (128 ± 3 mm Hg). The similar BP values were also observed in female rats of the study populations. The weight of the heart of male hybrids F4. F5, and F6 was more than that in the WKY group (1,17 ± 0,03, 1,01 ± 0,04, and 1,19 ± 0,03 g, respectively, and 0,89 ± 0303 g, at p < 0,05 in WKY rats), but less than the values for the SHR group (1,38 ± 0,11 g, p < 0,05). The experimental model may be interesting and useful in solving a variety of physiological, genetic, and pharmacological problems.

Age‐Related Analysis of Glucose Metabolism in Spontaneously Hypertensive and Normotensive Rats

This study was designed to investigate the effect of both hypertension and ageing on the efficiency of glucose metabolism. A 12-sample, 120 min intravenous glucose tolerance test (IVGTT) was applied to 36 rats: two groups of nine young (12 weeks) spontaneously hypertensive and Wistar Kyoto rats (Y-SHR and Y-WKY group, respectively) and two groups of nine old (40 weeks) SHR and WKY rats (O-SHR and O-WKY group, respectively). Insulinaemia and glycaemia data were interpreted in terms of estimates of glucose effectiveness, S(G), and insulin sensitivity, S(I), provided by the minimal model of glucose kinetics. The possible link between insulin resistance and hypertension was investigated by comparing Y-SHR vs. Y-WKY and O-SHR vs. O-WKY groups. Comparison of O-SHR vs. Y-SHR and O-WKY vs. Y-WKY groups enabled us to investigate the role of age in the development of abnormalities in glucose metabolism. No significant differences (P > 0.05) were observed in the mean S(G) and S(I) estimates between SHR and age-matched WKY groups. This finding indicates that exposure of SHR to high blood pressure levels does not necessarily lead to the development of insulin resistance and impaired glucose effectiveness. Similarly, no significant differences (P > 0.05) were observed in S(G) and S(I) estimates between old and young SHR and WKY groups. This finding indicates that, in this animal model of hypertension, insulin sensitivity and glucose effectiveness do not even deteriorate with ageing.

Cardiac hypertrophy by hypertension and exercise training exhibits different gene expression of enzymes in energy metabolism.

Hypertension-induced pathological cardiac hypertrophy (hypertensive heart) and exercise training-induced physiological cardiac hypertrophy (athletic heart) have differences in cardiac properties. We hypothesized that gene expression of energy metabolic enzymes differs between these two types of cardiac hypertrophy. To investigate whether mRNA expression of key enzymes in the long-chain fatty acid (FA), glucose, and lactic acid metabolic pathways differs between these two types of cardiac hypertrophy, we used the hearts of spontaneously hypertensive rats (SHR; 19 weeks old) as a model of the hypertensive heart, swim-trained rats (Trained; 19 weeks old, swimming training for 15 weeks) as a model of the athletic heart, and sedentary Wistar-Kyoto rats (Control; 19 weeks old). SHR developed hypertensive cardiac hypertrophy, of which cardiac function was deteriorated, whereas Trained rats developed an athletic heart, of which cardiac function was enhanced. The mRNA expression of CD36, which involved in uptake of long-chain FA, in the heart was almost never detected in the SHR group. Furthermore, the mRNA expression of key enzymes in the long-chain FA metabolic pathway (acyl CoA synthase [ACoAS], carnitine palmitoyl transferase [CPT]-I, CPT-II, and isocitrate dehydrogenase [ISCD]) in the heart was significantly higher in the SHR group compared with the Control group. The mRNA expression of ACoAS, CPT-I, ISCD, and CD36 in the heart did not differ between Trained group and Control group, whereas that of CPT-II in the Trained group was significantly higher compared with the Control group. The mRNA expression of key enzymes (phosphofructokinase and lactate dehydrogenase) in glycolytic metabolic pathway in the heart was markedly higher in the SHR group compared with the Control group, whereas these mRNA expressions did not differ between Trained group and Control group. These findings suggest that the molecular phenotypes in the energy metabolic system differ in hypertension-induced pathological and exercise training-induced physiological cardiac hypertrophy, and these differences may participate in the differences in cardiac function.

The effect of hypertension on uncontrolled hemorrhage in a rodent model.

Patients with essential hypertension (EH) have higher mortality rates from hemorrhage. How the complex physiologic changes seen in EH affect the response to uncontrolled hemorrhage has yet to be adequately described. To test the null hypothesis that there would be no difference in the hemorrhage volumes and hemodynamic responses to uncontrolled hemorrhage between hypertensive rats (SHRs) and normotensive rats (WKYs). Twenty-four adult rats (12 WKYs and 12 SHRs) were anesthetized with althesin via the intra-peritoneal route. The femoral artery was cannulated by cutdown for mean arterial pressure (MAP) measurement and blood gas sampling. Twelve rats (6 WKYs and 6 SHRs) underwent uncontrolled hemorrhage by 50% tail amputation. Twelve rats (6 WKYs and 6 SHRs) served as non-hemorrhage controls. The MAP, base excess (BE), and cumulative blood loss were measured pre-hemorrhage and then every 15 minutes post-hemorrhage for 90 minutes. Data were reported as mean +/- standard error of the mean. Comparisons between control and uncontrolled hemorrhage groups were analyzed by analysis of variance (ANOVA) with repeated-measures post-hoc testing by Bonferroni. Statistical significance was defined by an alpha = 0.05. Mortality rates were significantly higher (p < 0.05) for the SHRs (100%) as compared with the WKYs (33%). Changes in time-averaged MAP post-hemorrhage were significantly greater (p < 0.001) in the SHR group (88 +/- 10 mm Hg) as compared with the WKY group (48 +/- 4 mm Hg). Hemorrhage volume was significantly lower (p = 0.02) in the SHR group (3.7 +/- 0.5 mL) as compared with the WKY group (6.1 +/- 0.7 mL). Hypertensive rats had a higher mortality rate than normotensives from a comparable vascular injury with lower hemorrhage volumes.

The Effect of Hypertension on Uncontrolled Hemorrhage in a Rodent Model

AbstractPatients with essential hypertension (EH) have higher mortality rates from hemorrhage. How the complex physiologic changes seen in EH affect the response to uncontrolled hemorrhage has yet to be adequately described. Objective: To test the null hypothesis that there would be no difference in the hemorrhage volumes and hemodynamic responses to uncontrolled hemorrhage between hypertensive rats (SHRs) and normotensive rats (WKYs). Methods: Twenty‐four adult rats (12 WKYs and 12 SHRs) were anesthetized with althesin via the intra‐peritoneal route. The femoral artery was cannulated by cutdown for mean arterial pressure (MAP) measurement and blood gas sampling. Twelve rats (6 WKYs and 6 SHRs) underwent uncontrolled hemorrhage by 50% tail amputation. Twelve rats (6 WKYs and 6 SHRs) served as non‐hemorrhage controls. The MAP, base excess (BE), and cumulative blood loss were measured pre‐hemorrhage and then every 15 minutes post‐hemorrhage for 90 minutes. Data were reported as mean ± standard error of the mean. Comparisons between control and uncontrolled hemorrhage groups were analyzed by analysis of variance (ANOVA) with repeated‐measures post‐hoc testing by Bonferroni. Statistical significance was defined by an alpha = 0.05. Results: Mortality rates were significantly higher (p &lt; 0.05) for the SHRs (100%) as compared with the WKYs (33%). Changes in time‐averaged MAP post‐hemorrhage were significantly greater (p &lt; 0.001) in the SHR group (88 ± 10 mm Hg) as compared with the WKY group (48 ± 4 mm Hg). Hemorrhage volume was significantly lower (p = 0.02) in the SHR group (3.7 ± 0.5 mL) as compared with the WKY group (6.1 ± 0.7 mL). Conclusions: Hypertensive rats had a higher mortality rate than normotensives from a comparable vascular injury with lower hemorrhage volumes.

Physiological and pathological cardiac hypertrophy induce different molecular phenotypes in the rat.

Pressure overload, such as hypertension, to the heart causes pathological cardiac hypertrophy, whereas chronic exercise causes physiological cardiac hypertrophy, which is defined as athletic heart. There are differences in cardiac properties between these two types of hypertrophy. We investigated whether mRNA expression of various cardiovascular regulating factors differs in rat hearts that are physiologically and pathologically hypertrophied, because we hypothesized that these two types of cardiac hypertrophy induce different molecular phenotypes. We used the spontaneously hypertensive rat (SHR group; 19 wk old) as a model of pathological hypertrophy and swim-trained rats (trained group; 19 wk old, swim training for 15 wk) as a model of physiological hypertrophy. We also used sedentary Wistar-Kyoto rats as the control group (19 wk old). Left ventricular mass index for body weight was significantly higher in SHR and trained groups than in the control group. Expression of brain natriuretic peptide, angiotensin-converting enzyme, and endothelin-1 mRNA in the heart was significantly higher in the SHR group than in control and trained groups. Expression of adrenomedullin mRNA in the heart was significantly lower in the trained group than in control and SHR groups. Expression of beta(1)-adrenergic receptor mRNA in the heart was significantly higher in SHR and trained groups than in the control group. Expression of beta(1)-adrenergic receptor kinase mRNA, which inhibits beta(1)-adrenergic receptor activity, in the heart was markedly higher in the SHR group than in control and trained groups. We demonstrated for the first time that the manner of mRNA expression of various cardiovascular regulating factors in the heart differs between physiological and pathological cardiac hypertrophy.

AT 1 Receptor Antagonist Combats Oxidative Stress in the JGA of the SHR

24 The tubuloglomerular feedback (TGF) responses of the SHR are under exaggerated regulation by angiotensin II (Ang II) type 1 receptors (AT 1 -R). Since AT 1 -R enhance oxygen radical (O 2 - ) generation, we tested the hypothesis that the exaggerated TGF was due to a diminished blunting by macula densa (MD)-derived nitric oxide (NO) because of excessive AT 1 -R-dependent generation of O 2 - . Groups (n=6-9) of SHR and control WKY rats received vehicle (Veh), the AT 1 -R antagonist candesartan (Cand; 3 mg·kg -1 ·d -1 ) or non-specific therapy with hydralazine + hydrochlorothiazide + reserpine (HHR) for two weeks. Compared to WKY, the elevated mean arterial pressure of SHR (WKY: 125±2 vs. SHR: 163±9 mmHg; p&lt;0.001) was reduced (p&lt;0.001) similarly in SHR by Cand and HHR (121±5 and 116±5 mmHg, ns). The SHR had an increased maximal TGF response (change in stop flow pressure during luminal perfusion of fluid: SHR; 11.2±0.5 vs. WKY; 8.3±0.4 mmHg; p&lt;0.01) and a reduced TGF response to blockade of neuronal (n) NOS in the MD with luminal 7-nitroindazole (7-NI: ΔTGF in WKY: +2.8±0.4 vs. SHR +1.1±0.6 mmHg; p&lt;0.05). Although the elevated TGF responses of SHR were normalized by both HHR and Cand, only Cand restored a normal TGF response to luminal perfusion of the MD with 7-NI (ΔTGF with 7-NI: +1.8±0.4 vs. Cand +3.4±0.5 mmHg; p&lt;0.05). To abrogate the local effects of O 2 - , tempol (a membrane-permeable superoxide dismutase mimetic) was perfused into the efferent arteriole. During tempol, SHR given vehicle or HHR had a much increased response to blockade of nNOS with 7-NI (ΔTGF with 7-NI during tempol: Veh, +6.3±1.0 and HHR, +4.5±0.8 mmHg; p&lt;0.01 vs. no tempol for both) implying that the effects of NO had been prevented because of excessive O 2 - . In contrast, the TGF response to 7-NI in SHR given Cand was unaffected by tempol (ΔTGF with 7-NI during tempol: +2.9±0.9; ns compared to no tempol). In conclusion, TGF responses of SHR are exaggerated due to effects of hypertension and AT 1 -R. AT 1 -R blockade specifically diminishes oxidative stress and restores NO signaling in the JGA of the SHR.

Intraluminal suture occlusion of the middle cerebral artery in Spontaneously Hypertensive rats

In models of middle cerebral artery occlusion using intraluminal suture, the size and the distribution of ischemic injury vary considerably among laboratories. In transcranial models of cerebral ischemia, a more consistent cerebral ischemic lesion is seen in Spontaneously Hypertensive rats (5HR). In the present study, we performed intraluminal suture occlusion ofthe MCA in SHR and compared its reproducibility with those in Sprague-Dawley (SD) rats. Male 5HR and SO rats were anesthetized with halothane and subjected to 2 h of temporary middle cerebral artery occlusion by an intraluminal suture. Comparisons of regional cerebral blood flow figures taken throughout the experiment and lesion volume figures taken at 24 h after occlusion were made between the two groups. Total lesion volume in the SHR group was 263.6 ± 30.5 mm3 (mean ± SO), significantly larger and less variable than that in the SO group (145.4 ± 123.7mm3, p < 0.02). Throughout the ischemic period there was a tendency for rCBF to be lower in the 5HR group than in the SO group. In some animals of both groups, recirculation could not be produced by withdrawal of the suture from the ICA. The mortality rate was 9% in the SO group and 17% in the 5HR group. Intraluminal MeA occlusion in 5HRs is associated with a more consistent, reliable and reproducible volume of ischemic injury. In the studies of temporary focal cerebral ischemia, this model must be accompanied by the monitoring of regional cerebral blood flow so as to obtain more reliable results. [Neural Res 1998; 20: 265-270]

Comparison of the contractile performance of the hypertrophied myocardium from spontaneous hypertensive rats and normotensive infarcted rats

The sarcoplasmic reticulum (SR) exerts a key role on the excitation-contraction coupling process in the myocardium. Since the relation between the volume of cellular organelles, such as SR, and the sarcolemmal area of myocytes is not uniform in myocardial hypertrophy of different etiologies, we compared the contractile performances of hypertrophied left ventricular papillary muscles from rats with pressure overload and with volume overload. Hemodynamically compensated spontaneous hypertensive rats (SHR, 3 months old, systolic blood pressure = 189 ± 4 mmHg, n = 8) and Wistar rats with healed (30 days) myocardial infarction (MI, n = 7) produced by ligation of the left coronary artery were used. Results were compared with age-matched Wistar control (CON) rats (n = 13). Force (F), corrected to muscle cross-sectional area (g/mm2), and dF/dt were recorded in muscles contracting isometrically and stretched to Lmax. The inotropic response to increasing extracellular Ca2+ concentrations (1.25 to 5.0 mM) was compared in twitches (0.5 Hz) and during tetanic stimulation (5 Hz, 30 s) in the muscles treated with 1 µM ryanodine. F recorded in basal conditions (Ca = 1.25 mM, 0.5 Hz) in the CON group (1.34 ± 0.20 g/mm2) was higher (p &lt; 0.05) than in the MI (0.73 ± 0.13 g/mm2) and lower (p &lt; 0.05) than in the SHR group (2.08 ± 0.25 g/mm2). Similar differences between groups were also observed in relation to +dF/dt. Increasing extracellular Ca produced a parallel increase of F and +dF/dt in the three groups of muscles. Ryanodine treatment reduced F and +dF/dt in all groups and completely inhibited the development of force in post-rest contractions, indicating SR inhibition. SHR muscles were more sensitive to ryanodine than CON and MI (F decrease = 64 ± 7, 51 ± 5, and 22 ± 5%, respectively, p &lt; 0.05). The tetanic tension (Ca = 1.25 mM) was similar in SHR and CON (0.82 ± 0.19 and 0.92 ± 0.18 g/mm2; p &gt; 0.05) and depressed in the MI group (0.35 ± 0.12 g/mm2). These data suggest an increased participation of SR as source of activator Ca in the hypertrophied muscle of SHR. This adaptation likely contributes to maintain the normal cardiac function in hemodynamically compensated SHR, despite increasing afterload levels. This adaptation seems not to occur after MI, which may contribute to the depressed contractile performance of the left ventricular muscle surviving to infarction.Key words: myocardial contractility, myocardial hypertrophy, sarcoplasmic reticulum, myocardial infarction, hypertension.

Comparison of the contractile performance of the hypertrophied myocardium from spontaneous hypertensive rats and normotensive infarcted rats

The sarcoplasmic reticulum (SR) exerts a key role on the excitation-contraction coupling process in the myocardium. Since the relation between the volume of cellular organelles, such as SR, and the sarcolemmal area of myocytes is not uniform in myocardial hypertrophy of different etiologies, we compared the contractile performances of hypertrophied left ventricular papillary muscles from rats with pressure overload and with volume overload. Hemodynamically compensated spontaneous hypertensive rats (SHR, 3 months old, systolic blood pressure = 189 +/- 4 mmHg, n = 8) and Wistar rats with healed (30 days) myocardial infarction (MI, n = 7) produced by ligation of the left coronary artery were used. Results were compared with age-matched Wistar control (CON) rats (n = 13). Force (F), corrected to muscle cross-sectional area (g/mm2), and dF/dt were recorded in muscles contracting isometrically and stretched to Lmax. The inotropic response to increasing extracellular Ca2+ concentrations (1.25 to 5.0 mM) was compared in twitches (0.5 Hz) and during tetanic stimulation (5 Hz, 30 s) in the muscles treated with 1 microM ryanodine. F recorded in basal conditions (Ca = 1.25 mM, 0.5 Hz) in the CON group (1.34 +/- 0.20 g/mm2) was higher (p < 0.05) than in the MI (0.73 +/- 0.13 g/mm2) and lower (p < 0.05) than in the SHR group (2.08 +/- 0.25 g/mm2). Similar differences between groups were also observed in relation to +dF/dt. Increasing extracellular Ca produced a parallel increase of F and +dF/dt in the three groups of muscles. Ryanodine treatment reduced F and +dF/dt in all groups and completely inhibited the development of force in post-rest contractions, indicating SR inhibition. SHR muscles were more sensitive to ryanodine than CON and MI (F decrease = 64 +/- 7, 51 +/- 5, and 22 +/- 5%, respectively, p < 0.05). The tetanic tension (Ca = 1.25 mM) was similar in SHR and CON (0.82 +/- 0.19 and 0.92 +/- 0.18 g/mm2; p > 0.05) and depressed in the MI group (0.35 +/- 0.12 g/mm2). These data suggest an increased participation of SR as source of activator Ca in the hypertrophied muscle of SHR. This adaptation likely contributes to maintain the normal cardiac function in hemodynamically compensated SHR, despite increasing afterload levels. This adaptation seems not to occur after MI, which may contribute to the depressed contractile performance of the left ventricular muscle surviving to infarction.

Hyperinsulinemia Induces Myocardial Infarctions and Arteriolar Medial Hypertrophy in Spontaneously Hypertensive Rats

To investigate the effects of hyperinsulinemia on the myocardial vessels, long acting insulin (mixtard, a combination of 30% regular human insulin and 70% NPH human insulin) was injected daily for 8 weeks, intraperitoneally, in two strains of rats, normotensive WKY and hypertensive SHR. There were four groups in all, a control group, and an insulin-injected group in each strain. The drinking water contained 10% glucose to prevent hypoglycemia in the insulin-injected rats. At the end of the 8 weeks experimental period, after measuring blood pressure and taking blood for the determination of glucose, urea, creatinine, and insulin, the rats were killed. The organs were fixed in formaldehyde. The blood glucose levels were higher at the end of the experiment, in both the placebo-(saline)-injected and the insulin-injected rats. Blood pressure rose significantly only in the insulin-injected SHR. The intramyocardial arterioles in the insulin-injected SHR had a significantly thicker vascular wall than the placebo-injected SHR, as represented by the vessel wall to lumen ratio, because of hypertrophy of the media. When compared with the placebo injected WKY rats, there was a higher wall/lumen ratio of the intramyocardial arterioles in the insulin-injected WKY, but the difference did not reach significance. Heart weights factored by body weights was significantly higher in insulin-injected as compared with placebo-injected SHR. Myocardial infarctions were observed in four of eight rats in the insulin-injected SHR group despite the fact that there were no signs of atherosclerosis or intimal thickening. It is possible that the increase in heart weight and the probable increase in metabolic activity resulting from hyperinsulinemia, together with the increased oxygen demand of the myocardium and the arteriolar narrowing, may have contributed to the occurence of myocardial infarctions in the absence of atherosclerotic coronary occlusion.

Electromyography data on spontaneously hypertensive rats.

1. To investigate the state of nerve-muscle excitability in 20 spontaneously hypertensive rats and 22 Wistar rats local electromyography was carried out in periods of rest and under the maximum strain of 10 min ischaemia of m.flexor femoris (Trusso's test). 2. The electromyography phenomenon found in the SHR group corresponds to typical tetany electromyography correlatives. 3. Thus, changes occur to the nerve-muscle excitability state according to the neurogenic tetany type.

Enhanced circulating levels of neurally derived calcitonin gene related peptide in spontaneously hypertensive rats

Calcitonin gene related peptide (CGRP) is a potent endogenous vasodilator. The peptide is released from perivascular nerve endings and can normally be detected in the circulation. An attempt was made to determine the concentrations and partially characterise the immunoreactive forms of circulating CGRP in a genetically hypertensive rat strain, the "spontaneously hypertensive rat" (SHR) and its genetic control, Wistar-Kyoto (WKY). Immunoreactive plasma CGRP levels were measured using a highly sensitive carboxyl terminal specific CGRP radioimmunoassay together with high performance liquid chromatography. Plasma immunoreactive CGRP (i-CGRP) levels were also measured 6 h after intraperitoneal colchicine administration (10 mg.kg-1 body weight) to both groups of rats. Eight SHR rats were compared with eight WKY rats, both groups aged 7 weeks. Mean i-CGRP levels were threefold higher in the SHR group compared to controls, while plasma calcitonin levels were not different between the two groups. There was a significant correlation (Kendall's correlation coefficient, r = 0.57; p = 0.024) between i-CGRP levels and the mean systolic blood pressure (measured by the indirect tail cuff method) in SHR but not WKY rats. Similar profiles of i-CGRP were observed in both SHR and WKY rats, when acid-methanol extracts of pooled plasma were chromatographed under similar conditions. It was also confirmed that circulating CGRP in both SHR and WKY strains was derived from perivascular nerve endings, by demonstrating a complete abolition from plasma of previously detectable i-CGRP following the administration of colchicine. The study shows that CGRP is normally released from vascular nerve endings, and that high concentrations of the circulating peptide are found in hypertension. This might represent a mechanism to counteract the excessive vasoconstrictor influences that underly the development and maintenance of hypertension.

Naloxone Induced Enhancement of Systolic Blood Pressure and Reduction of Hypothalamic Catecholamine Levels in Male SHR

These results demonstrated that Nal enhanced BP both Int and Cast male and female SHR but, the significant increase appeared only in castrated male and female SHR, suggesting that brain opiates increased by a lack of negative feed-back mechanisms due to Cast (it may be increased GTH), thus, the BP led to decreasing. Reasonably Nal act to inhibited the activity of brain opiate system, then the BP appeared as increasing. In correlation between BP and hypothalamic NE in groups of Int and Cast SHR, when hypothalamic NE was increased, the BP showed lower value, meaningly, while BP increased with Nal, hypothalamic NE decreased. However, though the pressor response by Nal was significantly higher in Cast-group than that of Int-group, the decreasing rate was lower in the former. Thus, sensitivity of hypothalamic NE to antihypertensive action was potensiated by castration. Resulting information with Epi was same as NE as above mentioned. Additionaly, it should be noted that content of Epi was 1/20 of NE.

Central and peripheral inhibition of angiotensin converting enzyme (ACE) in the SHR: correlation with the antihypertensive activity of ACE inhibitors.

A series of five structurally distinct ACE inhibitors were evaluated for their ability to inhibit tissue ACE activity in the SHR after oral administration. In the first series of experiments, the ACE inhibitors captopril, enalapril, pentopril, CGS 14824A and CGS 16617 were given to groups of SHR at doses that produced a 15 to 20 mm Hg reduction in blood pressure within 1 hour. Under these conditions of dose and time, only captopril significantly inhibited brain ACE activity (43%), whereas inhibition of serum ACE activity ranged from 72% to 99% with these agents. Inhibition of aortic ACE activity ranged from 54% to 87%, and lung ACE inhibition varied from 50% to 83%. In the second series of experiments, SHR were administered higher doses of each ACE inhibitor such that these compounds produced peak reductions in blood pressure (-25 mm Hg to -33 mm Hg) within a range of 2 to 6 hours. When tissue ACE activity was measured at the time corresponding to peak reduction in blood pressure, all five ACE inhibitors produced a significant inhibition of brain ACE activity ranging from 21% to 76%. Serum ACE activity was almost completely inhibited by these agents, with the exception of captopril (62% inhibition). The inhibition of aortic ACE activity ranged from 79% to 99%, while the inhibition of lung ACE activity did not increase under these conditions. These data suggest that ACE inhibitors may exert their maximal antihypertensive effects by inhibiting ACE in vascular tissues and brain.

Functional and metabolic properties in hearts from aged spontaneously hypertensive rats.

The effect of long-term pressure overload on myocardial functional and metabolic alterations was investigated in hearts from spontaneously hypertensive rats of 16 weeks (young SHR) and 44 weeks (aged SHR) and age matched normotensive Wistar Kyoto strain rats (young WKY, aged WKY). The hearts were perfused by working heart mode and whole heart ischemia was induced by one-way valve. Following 20 min of ischemia, the hearts were reperfused for 30 min. The heart-body weight ratio in both SHR groups was significantly higher than in the respective age-matched WKY groups. Coronary flow relative to heart weight in both SHR groups was significantly lower than that of the respective age-matched WKY during both preischemic and reperfused periods. There was no significant difference in the recovery rate of cardiac output between young and aged WKY, whereas the young and aged SHR revealed significantly less recovery than their respective age-matched WKY. Tissue creatine phosphate and energy charge in both aged groups were significantly lower than in the young groups. These results indicate that long-term pressure overload increases susceptibility to ischemia and decreases the myocardial reserve presumably resulting from relative ischemia, whereas deterioration was minimal in the normotensive aged rat heart.

Attenuation of alpha-adrenergic responsiveness in hypoxic SHR.

Chronic exposure to hypoxia reduces the severity of hypertension in SHR. This study explored the possibility that hypoxic moderation of spontaneous hypertension is caused by a decrease in vascular responsiveness. In vitro studies were conducted with thoracic aortic rings obtained from SHR and Wistar-Kyoto (WKY) rats maintained under hypoxic (H; simulated altitude = 3658 m) and normoxic (N; laboratory altitude = 1520 m) conditions. Vessels were removed prior to the rapid development of hypertension (5 weeks of age; 3 days of altitude exposure), during the rapid hypertension-development stage (10 weeks of age; 5 weeks of altitude exposure), and during the established hypertension stage (18 to 20 weeks of age; 11 to 13 weeks of altitude exposure). Dose-response curves were obtained using a non-specific vasoconstrictor (KCl) and an alpha-adrenergic agonist, phenylephrine. At all ages, WKY vessels developed greater maximal contraction to vasoconstrictor stimuli, whereas vessels from the two older groups of SHR were more sensitive (more responsive at lower dosages) to KCl. Hypoxia caused significant (p less than 0.05) attenuation of the contractile responses to phenylephrine in young "pre-hypertensive" SHR, while similar, though less marked, attenuation of phenylephrine responsiveness was evident in young WKY-H. Chronically-reduced responsiveness to phenylephrine was found in vessels from SHR-H but not WKY-H. The lack of hypoxia-induced changes in vessel response to the non-specific vasoconstrictor, KCl, suggests a specific hypoxic attenuation of adrenergic vascular responsiveness. Thus, hypoxia may protect against the development of spontaneous hypertension through attenuation of alpha-adrenergic vasoconstrictor mechanisms.

Reactivity to bradykinin and potassium of the isolated duodenum from rats with genetic and renal hypertension.

The biphasic (relaxation-contraction) response of the isolated duodenum was used to study the reactivity of non-vascular smooth muscles in genetic (SHR) and renal hypertensive rats compared to their respective controls (WKY and Wistar). For the contractile component of the response to bradykinin, the duodenum from WKY rats was more sensitive, whereas the duodenum from SHR was both more sensitive and hyperreactive, compared to that from Wistar rats. The relaxant component of the response to bradykinin was present in the duodenum of both WKY rats and SHR, but was concentration-dependent only in the WKY group. The relaxant response to K+ was very small in SHR, and was not concentration-dependent. The concentration-response curves for relaxant responses to adrenaline and for contractile responses to acetylcholine did not differ in the SHR and WKY groups. Ca2+/Mg2+-ATPase activity was found to be markedly reduced in the SHR group. No qualitative or quantitative differences were observed between the responses of the duodenum of renal hypertensive rats and those of their normotensive controls. It is proposed that the altered reactivity of the SHR duodenum is due to changes in ion handling by the smooth muscle cell membrane.